RGD Reference Report - A causative role for redox cycling of myoglobin and its inhibition by alkalinization in the pathogenesis and treatment of rhabdomyolysis-induced renal failure.

General

A causative role for redox cycling of myoglobin and its inhibition by alkalinization in the pathogenesis and treatment of rhabdomyolysis-induced renal failure.
Authors:	Moore, KP Holt, SG Patel, RP Svistunenko, DA Zackert, W Goodier, D Reeder, BJ Clozel, M Anand, R Cooper, CE Morrow, JD Wilson, MT Darley-Usmar, V Roberts LJ, 2ND
Citation:	Moore KP, etal., J Biol Chem. 1998 Nov 27;273(48):31731-7.
RGD ID:	7244259
Pubmed:	PMID:9822635 (View Abstract at PubMed)
Muscle injury (rhabdomyolysis) and subsequent deposition of myoglobin in the kidney causes renal vasoconstriction and renal failure. We tested the hypothesis that myoglobin induces oxidant injury to the kidney and the formation of F2-isoprostanes, potent renal vasoconstrictors formed during lipid peroxidation. In low density lipoprotein (LDL), myoglobin induced a 30-fold increase in the formation of F2-isoprostanes by a mechanism involving redox cycling between ferric and ferryl forms of myoglobin. In an animal model of rhabdomyolysis, urinary excretion of F2-isoprostanes increased by 7.3-fold compared with controls. Administration of alkali, a treatment for rhabdomyolysis, improved renal function and significantly reduced the urinary excretion of F2-isoprostanes by approximately 80%. EPR and UV spectroscopy demonstrated that myoglobin was deposited in the kidneys as the redox competent ferric myoglobin and that it's concentration was not decreased by alkalinization. Kinetic studies demonstrated that the reactivity of ferryl myoglobin, which is responsible for inducing lipid peroxidation, is markedly attenuated at alkaline pH. This was further supported by demonstrating that myoglobin-induced oxidation of LDL was inhibited at alkaline pH. These data strongly support a causative role for oxidative injury in the renal failure of rhabdomyolysis and suggest that the protective effect of alkalinization may be attributed to inhibition of myoglobin-induced lipid peroxidation.

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Term	Qualifier	Evidence	With	Reference	Notes	Source	Original Reference(s)
acute kidney failure		ISO	Mb (Rattus norvegicus)	7244259; 7244259		RGD
acute kidney failure		IDA		7244259		RGD

Objects Annotated

Genes (Rattus norvegicus)

Mb (myoglobin)

Genes (Mus musculus)

Mb (myoglobin)

Genes (Homo sapiens)

MB (myoglobin)

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A causative role for redox cycling of myoglobin and its inhibition by alkalinization in the pathogenesis and treatment of rhabdomyolysis-induced renal failure.